—  SLIDE SEMINAR #10  —

Head and Neck Pathology
Moderators: Dr. Christina MacMillan and Dr. Nina Gale

Case 8 - Favor Atypical Parathyroid Adenoma with Cystic Degeneration and Prior Rupture

Dr. Jennifer Hunt


Case History:
A 75-year old woman presented with a mass in the neck and swallowing symptoms. She was found to be mildly hypercalcemic and a sestamibi scan identified an enlarged parathyroid gland located next to the esophagus. Intra-operatively the surgeon reported that the gland was very difficult to remove because it was extensively adherent to the esophagus and the vertebral fascia. An en bloc resection was performed.


Case 8 - Slide 1
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Diagnosis before additional history: Favor parathyroid carcinoma

Additional history obtained after surgery, frozen section, and final diagnosis:
The patient had trauma to the neck 1 year prior to surgery due to a motor vehicle accident. Scans revealed a large cystic mass near the esophagus that had ruptured. A week later, she experienced severe bruising of the neck and chest that seemed to be unrelated to the actual physical insult.

Diagnosis after additional history: Favor atypical parathyroid adenoma with cystic degeneration and prior rupture.

Case Eight Discussion
Hyperparathyroidism is relatively common with some estimates of incidence in European countries of 3-4 per 1,000 [40]. Comparable numbers would be expected in the United States [40, 41]. Causes of hyperparathyroidism are primary, secondary, or tertiary (TABLE 2) [40, 42]. Patients with hyperparathyroidism can be asymptomatic with hypercalcemia identified on routine health screens, or they may be very symptomatic with an increased risk of hypertension, nephrolithiasis, osteoporotic fractures or cardiovascular complications [42, 43, 44].

TABLE 2: Causes of hyperparathyroidism
Type Description Causes
Primary Hyperparathyroidism Parathyroid related disease Parathyroid adenoma
Parathyroid hyperplasia (genetic)
Parathyroid carcinoma
Secondary Hyperparathyroidism Secretion of parathyroid hormone in response to low calcium from another disease Rickets (Osteomalacia) due to vitamin D or calcium deficiency)
Sprue
Chronic renal failure
Tertiary Hyperparathyroidism One parathyroid gland becoming autonomous after persistent secondary hyperparathyroidism



The treatment of most types of hyperparathyroidism is usually surgical [45, 46]. There are several known risks of surgery, including damage to the recurrent laryngeal nerve and permanent hypoparathyroidism [47]. Historically, abnormal or enlarged glands are surgically excised, the weight is obtained, and frozen sections are performed to confirm the presence of parathyroid tissue [48, 49]. In cases of adenoma or carcinoma, shave biopsy of at least one normal sized gland has been routinely practiced to rule out the possibility of unrecognized heterogeneous hyperplasia, which can result in operative failure and/or recurrent hyperparathyroidism.

Cysts
Parathyroid cysts are considered to be rare, with the exception of cystic degeneration of a parathyroid neoplasm. In one study of 25 years worth of parathyroid surgery (and over 22,000 thyroid and parathyroid specimens), 37 patients were identified to have parathyroid cysts [50]. Parathyroid cysts are usually non-functional, with only rare cases of hyperparathyroidism being reported with parathyroid cysts [51, 52, 53]. The cysts presented primarily as mass lesions, either as known parathyroid cysts (from fluid sampling with parathyroid hormone assays) or as "thyroid nodules" [54, 55]. The cysts are generally located in the neck, but also can extend into the mediastinum [56]. Other parathyroid lesions can also be found in the mediastinum [57].

Histologically, parathyroid cysts are usually lined by a non-descript epithelium that is low and cuboidal [58]. The epithelium may be vacuolated as well. In the wall of the cysts, there is usually some residual parathyroid tissue, forming typical nests. Parathyroid hormone immunohistochemistry stains and CK19 will be positive, as will chromogranin and synaptophysin.

Interesting, parathyroid cysts are often associated with other types of tissue as well [50, 59]. This can include salivary gland heterotopia, thymic remnants, or other stromal elements (smooth muscle, adipose and fibrous tissues). This raises the possibility that parathyroid cysts may represent hamartomas or benign embryologic rests [59].

The differential diagnosis for these lesions will include other neck cysts, particularly before histological sampling. The primary neck cysts that may be considered would be branchial cleft cyst, thyroglossal duct cyst, and thymic cysts [60]. These benign lesions range from common (branchial and thyroglossal duct cysts) to rare (thymic cysts). The histology and characteristic locations should help in making this diagnosis. But, in the case of overlapping features, a parathyroid hormone stain will certainly determine the true etiology of a parathyroid cyst.

One interesting association has been reported between cysts in parathyroid and the genetic disease hyperparathyroidism—jaw tumor syndrome (HPT-JT). This syndrome is linked to a region of a presumed tumor suppressor gene on 1q32. When histologically sampled, many of the parathyroid lesions in these patients will be cystic and sometimes this syndrome may be referred to as cystic parathyroid adenomatosis [61]. Patients with this syndrome have an increased risk of developing carcinoma, which is seen in10-15% of patients with HPT-JT.

Adenoma and Carcinoma
The majority of patients with primary hyperparathyroidism will have a single glandular abnormality. These patients usually present with incidental hypercalcemia, found at routine health screenings. A sestamibi scan can help the surgeon to pre-operatively locate the abnormal gland, but these may be nonspecific and thus exploration during surgery may still be needed. In the setting of hyperparathyroidism, a single enlarged parathyroid gland will be surgically excised, in a conservative operation in order to not harm the recurrent laryngeal nerve or other critical structures in the neck. The other glands may be explored, particularly if there is a concern of the possibility of either double adenoma or asynchronous hyperplasia.

The first step in assessing a parathyroid gland it the determination if the gland is enlarged. Most people use the weight as the most accurate measurement of the size of a parathyroid gland [62]. The normal weight of the parathyroid gland should be less than 60 mg. But, in an autopsy study, normal glands had a median weight of 26 mg (range 8 to 75 mg); lower weights were seen in patients with chronic diseases [63]. Some investigators have also used the size of the gland, though standard measurements have not been nearly so well established [64].

Parathyroid adenomas are almost always enlarged by weights (i.e. > 60 mg). The mean weight of a parathyroid adenoma is around 500 mg (range 55 to >3000 mg) [62]. The parathyroid adenoma will have typical histologic findings. The cellular composition may include show predominantly a single cell type, or can show mixed features [62]. The most common type of cell to predominate is the chief cell, though oncocytes can also be dominant [57, 65, 66]. Occasionally parathyroid adenomas designated as "water clear cell adenomas" have been described in the literature. The cells in these lesions are composed of polygonal cells with very clear cytoplasm and distinct cytoplasmic borders [67]. Parathyroid hormone levels may be very low in these lesions [68]. Other morphologic features of parathyroid adenoma may include a rim of normal somewhat suppressed parathyroid tissue around the outside of the gland. This can be used as a diagnostic clue for the etiology of the pathologic process. Mitoses are usually rare to absent in parathyroid adenomas [69, 70].

The differential diagnosis between benign adenoma and carcinoma cannot be reliably made just based on the histologic assessment alone (TABLE 3). The surgeon's intraoperative opinion about adherence to surrounding structures is an important criterion in distinguishing benign from malignant parathyroid neoplasms. The surgeon who encounters a parathyroid carcinoma will describe the gland as "sticky," "fibrotic," "hypervascular," or "adherent to local structures" [71, 72]. These descriptions should immediately alert the pathologist to the possibility of parathyroid carcinoma. The histologic features of malignancy may not all be seen in a given case [70, 73]. There are some histopathologic features which are associated with malignancy, though they are certainly not pathognomonic for carcinoma. Worrisome features include the presence of increased or atypical mitoses, broad bands of fibrosis, trabecular growth pattern, invasion of adjacent tissue, and perineural or angiolymphatic invasion [74]. These features usually correlate with malignancy, though these histologic features are not always present in every case of parathyroid carcinoma [70, 75, 76]. Parathyroid carcinomas tend to be locally invasive and invasion is most commonly seen into the thyroid gland, strap muscles, recurrent laryngeal nerve, esophagus or trachea [70, 77].

TABLE 3: Clinical and histologic features of parathyroid carcinoma

Clinical Features Histologic Features
High calcium level (>14 mg/dl) Trabecular growth
Parathyroid hormone level > 5 x normal Broad intersecting fibrous bands
Palpable mass lesion Increased mitoses
Bone symptoms Stromal invasion
Operative findings of invasive growth (sticky, fibrotic, vascular gland) Angiolymphatic or perineural invasion



In the final analysis, it may be difficult to make a diagnosis of parathyroid carcinoma. In some cases, the clinical impression of parathyroid cancer does not correlate with the pathologic or microscopic impression. Therefore these cases are often labeled as "atypical adenoma", and because of diagnostic ambiguity, the true diagnosis may only be resolved with long term follow-up [70, 78].

The differential diagnosis for an atypical parathyroid lesion with histologic features worrisome for malignancy can include parathyroid adenomas or cyst that undergo degenerative changes from rupture or trauma; sometimes these features are also seen in the re-operative setting or in persons with neck surgery for other reasons. The presence of hemosiderin and degenerative changes can be helpful in making this diagnosis [70]. Parathyroid cyst rupture can be accompanied by an unusual clinical finding of hematoma and subsequent severe skin bruising [79]. Finally, in patients who have primary parathyroid surgery with spillage during the operation, parathyromatosis can develop [80]. In this condition, remnant parathyroid nests and clusters can be located throughout the neck tissues [81].

For many years, parathyroid carcinoma was thought of as a lethal disease with a terrible prognosis. This prognosis was probably partially related to non-uniform treatment and incomplete excision in some patients. The treatment of choice for parathyroid carcinoma is an en bloc resection with clear margins [73]. Most series of patients with parathyroid carcinoma with optimal treatment have shown recurrence rates of <10% and 5-year survivals of nearly 90% (~65-70% survival at 10-years) [77, 82]. Part of the reason behind the misconceptions about prognosis is the fact that some cases of parathyroid carcinoma have minimal invasion and very few other features of malignancy. These probably represent the lowest grade form of the disease, but no grading system is in place. At the other end of the spectrum will be rare patients who have aggressive malignancies with widespread invasion. One recent report suggested classifying minimally invasive tumors as low grade and widely invasive tumors as high grade [83].

There have been some studies of the molecular mutational findings in parathyroid neoplasia. One feature that is consistently noted is that parathyroid adenomas and carcinomas have a high rate of loss of the short arm of chromosome one (1p) [61, 84, 85, 86, 87]. This is not a feature that is generally seen in parathyroid hyperplasia. Other genes have also been implicated in parathyroid adenomas and carcinomas, including Retinoblastoma (RB, 13q14.3), the MEN gene (11q13), and the BRCA2 gene (13q12.3) [88, 89, 90]. Studies of a very interesting syndrome (hyperparathyroidism—jaw tumor syndrome) have also provided insight into the pathogenesis of parathyroid neoplasia. A tumors suppressor gene has been identified, mapping to 1q25-31 and designated as HPRT2 that harbors germline mutations in hereditary cases of this syndrome. But, loss of heterozygosity and somatic point mutations have also been detected in sporadic parathyroid carcinomas [91, 92]. The burden of loss of heterozygosity type of mutations across s a series of tumor suppressor genes has also been shown to correlate with the presence of malignancy [93].

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